Cycloalka[4,5]pyrrolo[2,3-g]isoquinolines

ABSTRACT

Neuroleptically active cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of the formula ##STR1## wherein n, R 1 , R 2  and X are as hereinafter set forth, are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 216,116, filed Dec. 15, 1980, now abandoned, which in turn is aContinuation-in-Part of U.S. Pat. application Ser. No. 125,604, filedFeb. 28, 1980, now abandoned.

BRIEF SUMMARY OF THE INVENTION

The invention relates to cycloalka[4,5]pyrrolo[2,3-g]isoquinolines ofthe formula ##STR2## wherein R₁ is hydrogen, alkyl, acyl or aralkyl; R₂is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl,acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkylalkyl, alkynyl,thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, aralkenyl,alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, oraryl-N-imidazolonylalkyl; X is O or S; and n is 3, 4, 5 or 6,

and their pharmaceutically acceptable acid addition salts.

In yet another aspect, the invention relates to intermediates of theformula ##STR3## wherein n is 3, 4, 5 or 6.

In still another aspect, the invention relates to intermediates of theformula ##STR4##

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to cycloalka[4,5]pyrrolo[2,3-g]isoquinolines ofthe formula ##STR5## wherein R₁ is hydrogen, alkyl, acyl or aralkyl; R₂is hydrogen, alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl,acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl, alkynyl,thienyl-alkyl, furyl-alkyl, arylcarboxamidoalkyl, aralkenyl,alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, oraryl-N-imidazolonylalkyl; X is O or S; and n is 3, 4, 5 or 6,

and their pharmaceutically acceptable acid addition salts.

As used herein, the term "alkyl" preferably denotes "lower alkyl", whichdenotes a straight or branched chain saturated hydrocarbon containing 1to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl,t-butyl, neopentyl, pentyl, heptyl, and the like. The term "cycloalkyl"denotes a cyclic alkyl group of 3 to 6 carbon atoms, for example,cyclopropyl, cyclohexyl, and the like. The term "alkoxy", preferablydenotes "lower alkoxy", which denotes an alkyl ether group in which thelower alkyl group is as described above, for example, methoxy, ethoxy,propoxy, pentoxy, and the like. The term "alkenyl" preferably denotes"lower alkenyl", which denotes a straight or branched chain unsaturatedhydrocarbon containing 2 to 7 carbon atoms, for example, vinyl, allyl,and the like. The term "alkenyloxy", preferably denotes "loweralkenyloxy", which denotes an alkenyl ether group in which the loweralkenyl group is as described above, for example, ethenyloxy, and thelike. The term "alkynyl" preferably denotes "lower alkynyl", whichdenotes a straight or branched chain unsaturated hydrocarbon containing2 to 7 carbon atoms, for example, ethynyl, propargyl, methylbutynyl, andthe like. The term "halogen" or "halo" denotes all the halogens, i.e.,bromine, chlorine, fluorine, and iodine. The term "aryl" denotes phenylor phenyl bearing one or more substituents selected from the groupconsisting of halogen, trifluoromethyl, lower alkyl, lower alkoxy,nitro, amino, lower alkylamino, and di-lower alkylamino. The term"aralkyl" preferably denotes an aryl group linked to an alkylene chainof 1 to 4 carbon atoms, such as, 2-phenylethyl, 4-chlorobenzyl, benzyland the like. The term aralkenyl preferably denotes 3-phenyl-2-propenyl,and the like. The term "aralkyloxy" denotes an aralkyl ether, forexample, benzyloxy, and the like. The term "aryloxy" denotes an arylether group in which the aryl group is as described above, for example,phenoxy, and the like. The term "acyl" denotes an "alkanoyl" groupderived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, forexample, formyl, acetyl, propionyl, and the like; and an "aroyl" groupderived from an aromatic carboxylic acid, such as benzoyl,4-fluorobenzoyl and the like. The term "acyloxy" denotes an"alkanoyloxy" group derived from an aliphatic carboxylic acid of 1 to 7carbon atoms, for example, formyloxy, acetoxy, propionyloxy, and thelike; and an "aroyloxy" group derived from an aromatic carboxylic acid,such as benzoyloxy and the like. Exemplary of "acylalkyl" are2-oxopropyl, 4-(4-fluorophenyl)-4 oxobutyl and the like. Exemplary of"acyloxyalkyl" are 2-acetoxyethyl, 3-benzoyloxypropyl and the like.Exemplary of "hydroxyalkyl" are hydroxyethyl, 2-hydroxy-3,3-dimethybutyland the like. Exemplary of "cycloalkyl-alkyl" are cyclopropylmethyl,cyclobutylmethyl and the like. Exemplary of "arylcarboxamidoalkyl" arebenzamidoethyl and the like. Exemplary of "aryloxyalkyl" are3-phenoxypropyl and the like. Exemplary of "aralkyloxyalkyl" are2-benzyloxyethyl, 3-benzyloxypropyl and the like. Exemplary of"aryl-N-imidazolonylalkyl" are2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl,3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl and the like. Exemplaryof "arylhydroxyalkyl" are 2-hydroxy-2-phenylethyl,2-hydroxy-2-(4-chlorophenyl)ethyl and the like. Exemplary of"alkoxyalkyl" are 2-ethoxyethyl, 3-methoxypropyl and the like. Exemplaryof "alkenyloxyalkyl" are 2-ethenyloxyethyl and the like.

Preferred compounds of formula A are those wherein n is 3, 4, 5 or 6, R₁is hydrogen, R₂ is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl,aryloxyalkyl, acylalkyl, or aralkyl; and X is O or S.

More preferred compounds of formula A are those wherein n is 3 or 4, R₁is hydrogen, R₂ is alkyl, hydroxyalkyl, arylhyroxyalkyl, alkoxyalkyl,aryloxyalkyl, acylalkyl, or aralkyl; and X is O.

Most preferred compounds of formula A of the invention are:

2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-10(10H)-one;

2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onehydrochloride, 0.5 molar hydrate;

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

(-)-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]-pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahyro-4a,11a-trans-1H,6H-cyclohexa[4,5]-pyrrolo[2,3-g]isoquinolin-11(11H)-one,0.75 molar hydrate;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexsa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;and

2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-10(10H)-thione.

Exemplary of the compounds of formula A wherein n is 3, i.e., a compoundof the formula ##STR6## wherein R₁, R₂ and X are as previouslydescribed, are:2-ethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-10(10H)-one;

2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-(2-hydroxy-2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-(2-acetoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[3-(4-fluorophenyl)-3-oxopropyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(4-methoxyphenyl)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-allyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-[2,3-g]isoquinolin-10(10H)-one;

2-cyclopropylmethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-propargyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(2-thienyl)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(2-furyl)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(benzyloxy)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-(3-phenyl-2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(4-fluorobenzamido)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-[2-(ethylenyloxy)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2-benzyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

2,6-dimethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-10(10H)-one;

6-benzyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one;

6-methyl-2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3,-g]isoquinolin-10(10H)-one;

1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]-isoquinolin-10(10H)-thione;

2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione;

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione;and

2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione.

Exemplary of the compounds of formula A wherein n is 4, i.e., compoundsof the formula ##STR7##

wherein R₁, R₂ and X are as previously described, are:

2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-cyclobutylmethyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-[2-(2-thienyl)ethyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-[2-(2-furyl)ethyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-[3-(4-fluorophenyl)-3-oxopropyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-(2-propenyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2,6-dimethyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

6-benzoyl-2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-thione;

2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-thione;and

2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-thione.

In the compounds of formula A-2 wherein X is O, an alternativenomenclature may be employed. Thus, for example,

2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]-pyrrolo[2,3-g]isoquinolin-11(11H)-one;and

2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-pyrido[4,3-b]carbazol-11(1H,6H)-oneare one and the same compound.

Exemplary of the compounds of formula A wherein n is 5, i.e., compoundsof the formula ##STR8## wherein R₁, R₂ and X are as previouslydescribed, are:2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one;

2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one;

2-(3-phenoxypropyl)-1,2,3,4,4a,,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one;

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one;

2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-thione;

2-(3-phenoxypropyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-thione;and

2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-thione.

Exemplary of the compounds of formula A wherein n is 6, i.e., compoundsof the formula ##STR9## wherein R₁, R₂ and X are as previouslydescribed, are:2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;

2-(2-hydroxy-3,3-dimethylpropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;

2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;

2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one;

2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione;

2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione;

2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione;and

2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-thione.

The compounds of the invention wherein n is 3 can exist as the4a,10a-trans or 4a,10a-cis isomers or mixtures thereof; the 4a,10a-transisomers are preferred.

The compounds of the invention wherein n is 4 can exist as the4a,11a-trans or 4a,11a-cis isomers or mixtures thereof; the 4a,11a-transisomers are preferred.

The compounds of the invention wherein n is 5 can exist as the4a,12a-trans or 4a,12a-cis isomers or mixtures thereof; the 4a,12a-transisomers are preferred.

The compounds of the invention wherein n is 6 can exist as the4a,13a-trans or 4a,13a-cis isomers or mixtures thereof; the 4a,13a-transisomers are preferred.

More specifically, the compounds of formula A wherein X is O arecharacterized by the formula ##STR10## wherein n, R₁ and R₂ are ashereinbefore described, and can be prepared as set forth in Schemes I,II, III and IV and further described. ##STR11## wherein n is aspreviously described, and R₂ " is alkyl, alkoxyalkyl, orcycloalkyl-alkyl.

In accordance with Formula Scheme I, compounds of formula Ia areprepared from known compounds of formula IV wherein R₂ " is alkyl,alkoxyalkyl or cycloalkylalkyl. Birch reduction of the amine of formulaIV with lithium in ammonia containing t-butanol yields the dihydroamineof formula V. Other modifications of the Birch reduction may also beemployed. Thus, the amine of formula IV may be reacted with an alkalimetal, such as sodium, lithium, potassium or cesium, in ammonia or anamine such as methylamine or ethylamine in the presence of a loweralkanol such as ethanol, butanol, or t-butanol. The reaction isgenerally carried out at the boiling point of the solvent or below, forexample, from -78° to 15° C. If ammonia is used, the reaction is run atreflux. Optionally, cosolvents such as diethyl ether or tetrahydrofuranmay be added.

The hydrolysis of the dihydroamine of formula V is readily accomplishedby the usual methods for hydrolysis of enol ethers, for example, withaqueous acid. Exemplary of acids which may be used are hydrochloricacid, hydrobromic acid, formic acid, acetic acid, p-toluenesulfonic acidand perchloric acid. These may be used in aqueous solutions or mixedsolvents. Tetrahydrofuran, benzene, diethyl ether, acetone, toluene,dioxane or acetonitrile are exemplary of the solvents which may beemployed. For example, hydrolysis of the dihydroamine of formula Vwherein R₂ " is methyl in 2 N hydrochloric acid at room temperature orabove or in aqueous acetic acid at between 40° and reflux leads to thediketone of formula VI, wherein R₂ " is methyl.

The diketone of formula VI is condensed in a Knorr condensation to givethe methylaminoethyl ketone of formula IX. The Knorr condensation is awell-known method for the preparation of pyrroles and the process may beused in any of the well-known modifications [see, for exemplaryconditions, J. M. Patterson, Synthesis, 281 (1976) and referencestherein]. For example, the reaction of an isonitrosoketone of formulaVII in the presence of a reducing agent, for example with zinc inaqueous acetic acid or hydrochloric acid, is thought to proceed via theaminocarbonyl compound of formula VIII which then condenses with thediketone of formula VI to give the product methylaminoethyl ketone offormula IX. Alternatively, the condensation can be carried out with anaminocarbonyl compound of formula VIII or precursor thereof, such as anaminoketone hydrochloride salt, or a ketal derivative of an aminoketone.The use of a precursor of the aminoketone is preferred, since suchsubstances are prone to self-condensation. They may best be utilized insitu where the aminocarbonyl component is liberated in the presence ofthe diketone of formula VI. The aminocarbonyl component immediatelyreacts to form the compound of formula IX. It is not necessary toisolate the diketone of formula VI prior to carrying out the Knorrcondensation since the reaction conditions employed are sufficient tohydrolyze the dihydroamine of formula V to the diketone of formula VI.The Knorr condensation is best carried out at a pH of from about pH 2 topH 6. Much above pH 6, there is a considerable loss in yield due to theformation of self-condensation products of the aminocarbonyl compound offormula VIII.

Preferably, an isonitrosoketone of formula VII and zinc dust in aqueousacetic acid is condensed with a diketone of formula VI wherein R₂ " ismethyl to give the product methylaminoethyl ketone of formula IX whereinR₂ " is methyl.

The Knorr condensation is preferably carried out at a temperature rangeof from about room temperature to reflux. The isonitrosoketones offormula VII are known compounds or can readily be prepared bynitrosation of the corresponding β-ketoester, for example, with sodiumnitrite. [see, for example, T. A. Geissman and M. J. Schlatter, J. Org.Chem., 11, 771 (1946)].

Exemplary of isonitrosoketones of formula VII which can be used in theKnorr condensation are:

2-isonitrosocyclopentanone;

2-isonitrosocyclohexanone;

2-isonitrosocycloheptanone; and

2-isonitrosocyclooctanone.

Exemplary of aminocarbonyl precursor compounds of formula VIII which canbe used in the Knorr condensation are:

2-aminocyclohexanone, hydrochloride;

2-aminocyclopentanone, hydrochloride;

2-aminocycloheptanone, hydrochloride; and

2-aminocyclooctanone, hydrochloride.

Said compounds are known or may be prepared by reduction of thecorresponding isonitrosoketone, for example, by catalytic hydrogenationin the presence of hydrogen chloride.

The amine of the formula IX is converted to the compound of the formulaIa via an intramolecular Mannich reaction. The Mannich reaction isusually performed starting with a ketone and a dialkylamine salt, forexample, dimethylamine hydrochloride and formaldehyde (for example, asan aqueous solution, as paraformaldehyde or as trioxane) in an alcoholicsolvent such as ethanol, at the reflux temperature of the reactionmixture. In the modification herein described, an acid addition salt ofthe methylaminoethyl-ketone of formula IX is reacted with formaldehyde,added in the form of paraformaldehyde, trioxane, or as aqueousformaldehyde in a solvent. For example, a high boiling hydroxylicsolvent, such as amyl alcohol, octanol, ethylene glycol or diethyleneglycol monoethyl ether; a high boiling polar aprotic solvent, such asdimethylformamide, N-methylpyrrolidinone or diethylene glycol dimethylether; a lower boiling polar solvent, such as ethanol, butanol or2-propanol, under pressure; or a lower boiling aprotic solvent underpressure, such as dioxane or tetrahydrofuran, may be used at atemperature in the range of from about 135° C. to about 200° C. to yieldthe cycloalka[4,5]pyrrolo[2,3-g]isoquinolines of formula Ia. Thereaction, especially when run at temperatures below 150° C. leads to amixture of cis and trans isomers, i.e., for example, when R₂ " ismethyl, compounds of the formulas ##STR12##

Longer heating of the reaction mixture or separate heating of theisomeric mixture of hydrochloride salts of formulas I'a and I"a, forexample, in ethylene glycol at reflux for 2 hours can be used toequilibrate the cis and trans isomers to a final ratio which comprisespredomonantly the trans isomer, which is readily isolated bycrystallization or by chromatographic separation.

For example, when the hydrochloride salt of the amine of formula IXwherein R₂ " is methyl is reacted with paraformaldehyde in butanol at180° for 2 hours, the product is isolated as the trans isomer I'a.##STR13## wherein n is as previously described, Y is a urethane group,and R₁ ' is alkyl, acyl or aralkyl.

In accordance with Formula Scheme II, compounds of formula Ic areprepared by alkylation or acylation or acylation of the pyrrole nitrogenof a compound of formula Ia' and other N-2-alkyl derivatives byformation of the pyrrole anion with strong base, for example, sodiumamide, potassium hydride, sodium methylsulfinyl carbanion, potassiumt-butoxide, or butyllithium, or with an alkali metal, followed byquenching with an alkyl or acyl halide in a solvent such astetrahydrofuran, dioxane, ethyl ether, dimethylformamide ordimethylsulfoxide. For example, treatment of a compound of formula Ia',wherein n is 3 with potassium t-butoxide in tetrahydrofuran followed byquenching with methyl iodide affords the 6-methyl derivative, i.e., acompound of formula Ic wherein n is 3 and R₁ ' is methyl. Similarly,reaction of a compound of formula Ia', wherein n is 4 with butyllithiumin tetrahydrofuran at -30° followed by quenching with benzoyl chlorideaffords the 6-benzoyl derivative, i.e., a compound of formula Ic whereinR₁ ' is benzoyl and n is 4. Similarly, reaction of a compound of formulaIa', wherein n is 3, with sodium methylsulfinyl carbanion indimethylsulfoxide followed by quenching with benzyl chloride affords the6-benzyl derivative, i.e., a compound of formula Ic wherein R₁ ' isbenzyl and n is 3. N-Demethylation of the compound of formula Ia' can beaccomplished by standard N-dealkylation procedures, such as the vonBraun method [H. A. Hageman, Org. Reactions, 7, 198 (1953)], or via acidor base hydrolysis of a urethane derivative such as those listed in K.C. Rice [J. Org. Chem., 40, 1850 (1975)]. One procedure for thedealkylation of the compound of formula Ia' is via the urethane offormula XIII, wherein Y is ##STR14## and acid hydrolysis, to give thesecondary amine of formula Ib. For example, a compound of formula Ia',wherein n is 4, when refluxed in dioxane with excess ethyl chloroformateand potassium bicarbonate for 6 hours gives a compound of formula XIII,wherein Y is ##STR15## and wherein n is 4. Hydrolysis of the foregoingcompound with 30% aqueous sodium hydroxide in ethanol-dioxane at refluxfor 24 hours gives the compound of formula Ib, wherein n is 4.

Urethane derivatives may also be employed as starting materials for thepreparation of pyrrole-ring substituted derivatives of formula Ie byalkylation or acylation at the pyrrole nitrogen, followed by cleavage ofthe urethane. The alkylation or acylation is carried out following theprocedures given for the preparation of compounds of formula Ic, and theurethane derivatives and procedures for their cleavage are given, asmentioned above, in K. C. Rice (ibid). For example, in accordance withFormula Scheme II, treatment of the ethoxycarbonyl urethane of formulaXIII, wherein Y is ##STR16## and n is 4 with sodium methylsulfinylcarbanion in dimethylsulfoxide, followed by treatment with benzylchloride, affords the compound of formula XIIIa, wherein Y is ##STR17##and n is 4 and R₁ ' is benzyl. Hydrolysis with sodium hydroxide affordsthe 6-benzyl derivative, i.e., a compound of the formula Ie wherein R₁ 'is benzyl and n is 4. In cases where R₁ ' is an acyl group which couldbe hydrolyzed under vigorous alkaline or strongly acidic conditions, aurethane group such as 2,2,2-trichloroethoxycarbonyl, which may becleaved under mild conditions with zinc in aqueous acetic acid, may beemployed to give compounds of formula Ie wherein R₁ ' is acyl. ##STR18##wherein n is as previously described, and R₁ ' is alkyl, acyl, oraralkyl, and R₂ ' is alkyl, hydroxyalkyl, arylhydroxyalkyl, alkoxyalkyl,acyloxyalkyl, acylalkyl, aralkyl, alkenyl, cycloalkyl-alkyl,thienyl-alkyl, alkynyl, furyl-alkyl, arylcarboxamidoalkyl, aralkenyl,alkenyloxyalkyl, aryloxyalkyl, aralkyloxyalkyl, oraryl-N-imidazolonylalkyl.

In accordance with Formula Scheme III, the compounds of formulas Id andIf are prepared from the secondary amine of formula Ib, the startingmaterial for the preparation of numerous derivatives encompassed byformula I, by substitution at the basic amine nitrogen (N-2) and/or thepyrrole nitrogen (N-6). For example, treatment of a compound of formulaIb with an alkyl halide, such as ethyl bromide, an alkenyl halide, suchas allyl bromide, a cycloalkyl-alkyl halide, such aschloromethylcyclopropane, an aralkyl halide, such as benzyl bromide, oran acylalkyl halide such as γ-chloro-p-fluorobutyrophenone, in thepresence of a base, for example, potassium carbonate, in acetone,2-propanone or dimethylformamide, yields the correspondingly substitutedcompound of formula Id, that is, when R₂ ' is alkyl, alkenyl,cycloalkyl-alkyl, aralkyl, or acylalkyl, respectively. With reactivehalides, the reaction may be run at room temperature; with less reactivehalides, reflux temperatures are used, and in some cases, the reactionrate can be enhanced by the addition of an iodide salt, such as lithiumiodide, to the reaction mixture.

Reaction of a compound of formula Ib with epoxyalkanes gives thehydroxyalkyl substituted compound of formula Id. Treatment with asubstituted epoxyalkane gives the 2-substituted-2-hydroxyalkyl analogsof a compound of formula Id, for example, reaction of a compound offormula Ib with styrene oxide gives a compound of formula Id, wherein R₂' is 2-phenyl-2-hydroxyethyl. The reaction is usually carried out in thepresence of an alcoholic solvent such as methanol, at from about roomtemperature to the reflux temperature of the mixture. The epoxyalkanesare either commercially available or are prepared by epoxidation of thecorresponding olefins, or by methylenation of a ketone with a sulfoniummethylide or sulfoxonium methylide reagent, for example,dimethylsulfonium methylide. Thus, for example, treatment ofbenzaldehyde with dimethylsulfonium methylide gives styrene oxide.

In some cases, where R₂ ' in the compound of formula Id does not containfunctional groups capable of undergoing alkylation or acylation, theprocedures outlined in Formula Scheme II for the preparation ofcompounds of formula Ic can be used directly to prepare N-6 substitutedanalogs of formula If as depicted in Formula Scheme III. Alkylations canoccur in compounds wherein R₂ ' is hydroxyalkyl or arylhydroxyalkyl. Thehydroxyl groups therein must be protected with a base-stable protectinggroup, such as tetrahydropyranyl. After N-6 alkylation, the protectinggroup is removed by acid hydrolysis.

Alternatively, compounds of formula Id, wherein R₂ ' is hydroxylalkyl oraryl hydroxyalkyl may be prepared by reduction of the correspondingcompounds of formula Id wherein R₂ ' is acylalkyl. More particularly,the foregoing reduction may be carried out, for example, with an alkalimetal borohydride reducing agent, such as sodium borohydride or lithiumborohydride at, for example, room temperature in a solvent, for example,an alkanol, such as ethanol, or the like.

In the reactions described in Formula Schemes I, II and III, both thetrans isomers of the formula ##STR19## wherein n, R₁ and R₂ are aspreviously described, and cis isomers of the formula ##STR20## whereinn, R₁ and R₂ are as previously described, of the compounds of formula Imay be formed, with the trans isomer predominating. The pure transisomer may be separated by chromatography or crystallization. Inaddition, the mixture may be isomerized as described for theisomerization of the trans and cis isomers of the oxo compound offormula I'a and I"a, or by base-catalyzed equilibration, for example,with sodium hydroxide in ethanol.

When the substituent groups R₁ and R₂ in compounds of the formula Icontain additional asymmetric centers, a mixture of diasteriomers may beobtained. For example, the number of isomers possible is 2^(n) wherein nis the total number of asymmetric centers in the compound. Preferred arethe enantiomers and/or diastereomers of compound of the formula I',hereinbefore described. ##STR21## wherein n is as previously described,and R₂ " is alkyl, alkoxy-alkyl, or cycloalkyl-alkyl.

An alternative synthesis of the compounds of formula Ia is described inFormula Scheme IV, in which the isoquinoline ring is formed prior to theformation of the pyrrole ring. In accordance with Formula Scheme IV, the(3,5-dimethoxyphenyl)-ethylamine of formula IV is refluxed with aqueousformaldehyde to give the tetrahydroisoquinoline of formula X. Birchreduction of the tetrahydroisoquinoline of formula X with lithium inliquid ammonia containing t-butanol under conditions substantially thesame as described for the Birch reduction of the compound of formula IVyields the hexahydroisoquinoline of formula XI. Hydrolysis of crudehexahydroisoquinoline of formula XI under conditions substantially thesame as described for the hydrolysis of the dihydroamine of the formulaV yields the diketone of formula XII. The compound of formula XII isreacted in a Knorr condensation, as described in the preparation of themethylaminoethyl ketone of formula IX with the isonitrosoketone offormula VII or with the aminocarbonyl compound of formula VIII to givethe cycloalka[4,5]pyrroloisoquinoline of formula Ia. Preferred is thesequence of reactions in accordance with Formula Scheme IV starting withthe amine of formula IV, wherein R₂ " is methyl, giving thecorresponding N-methyl-cycloalka[4,5]pyrroloisoquinoline of formula Ia,as a mixture containing the trans isomer I'a and the cis isomer offormula I"a.

The same procedures for isomerization of the mixture ofcycloalka[4,5]pyrroloisoquinolines of formulas I' and I" as describedpreviously may be employed to yield mainly the trans isomer of formulaI'a.

The compounds of formula A wherein X is S are characterized by theformula ##STR22## wherein n, R₁ and R₂ are as hereinbefore described,and can be prepared as set forth in Formula Schemes V and VI, andfurther described hereinafter. ##STR23## wherein n is as previouslydescribed; R₁ " is hydrogen, alkyl, or aralkyl; and R₂ "' is hydrogen,alkyl, alkoxyalkyl, aralkyl, alkenyl, aryloxyalkyl, thienylalkyl,furyl-alkyl, alkynyl, aralkenyl, alkenyloxyalkyl, aralkyloxyalkyl orcycloalkyl-alkyl.

In accordance with Formula Scheme V, compounds of formula IIa' areprepared by heating compounds of formula Ia' with phosphoruspentasulfide in an inert organic solvent. Preferred solvents aretetrahydrofuran, benzene, toluene or dioxane, and the reaction isgenerally run at the reflux temperature.

Additional compounds of formula II are prepared as described in FormulaScheme VI. In accordance with Formula Scheme VI, a compound of formulaIIb is reacted to give a compound of formula IId following theprocedures detailed in Formula Scheme III for the preparation of thecorresponding oxo compounds of formula Ib. ##STR24## wherein n, R₁ ' andR₂ ' are as previously described.

Similarly, a compound of formula IId is reacted to give a compound offormula IIf following the procedures outlined in Scheme III for thepreparation of the corresponding oxo compounds of formula If.

Additional compounds of formula II are prepared following the proceduresdetailed in Formula Scheme II for the preparation of corresponding oxocompounds of formula Ie.

In these reactions, both the trans isomers of the formula ##STR25##wherein n, R₁ and R₂ are as previously described, and cis isomers of theformula ##STR26## wherein n, R₁ and R₂ are as previously described, ofthe compounds of formula II may be formed, with the trans isomerpredominating. The pure trans isomer may be separated by chromatographyor crystallization. In addition, the mixture may be isomerized asdescribed for the isomerization of the trans and cis isomers of the oxocompound of formula I'a and I"a.

As described above for compounds of formula I, when substituent groupsR₁ and R₂ in compounds of formula II contain additional asymmetriccenters, a mixture of diastereomers may be obtained. Preferred are theenantiomers and/or diastereomers of compounds of the formula II',hereinbefore described.

The compounds of formula A form acid addition salts with inorganic ororganic acids. Thus, they form pharmaceutically acceptable acid additionsalts with both pharmaceutically acceptable organic and inorganic acids,for example, with hydrohalic acid, such as, hydrochloric acid,hydrobromic acid, hydroiodic acid, other mineral acid salts, such assulfuric acid, nitric acid, phosphoric acid, or the like, alkyl- andmono-aryl sulfonic acids, such as ethanesulfonic acid, toluenesulfonicacid, benzenesulfonic acid, or the like, other organic acids such asacetic acid, tartaric acid, maleic acid, citric acid, benzoic acid,salicylic acid, ascorbic acid, and the like. Non-pharmaceuticallyacceptable acid addition salts of compounds of formula A can beconverted into pharmaceutically acceptable acid addition salts viaconventional metathetic reactions whereby the non-pharmaceuticallyacceptable anion is replaced by a pharmaceutically acceptable anion; oralternatively, by neutralizing the non-pharmaceutically acceptable acidaddition salt and then reacting the so-obtained free base with a reagentyielding a pharmaceutically acceptable acid addition salt. The acidaddition salts may also form hydrates.

The compounds of formula A and their pharmaceutically acceptable acidaddition salt exhibit neuroleptic activity. Accordingly, the compoundsof formula A are useful as antipsychotic agents, for instance, in thetreatment of schizophrenia. The activity of the compounds of formula Awhich makes them useful as antipsychotic agents can be demonstrated inwarm-blooded animals, in accordance with known procedures.

For example, by one procedure, trained rats are placed in experimentalchambers equipped with a response lever, a steel grid floor for deliveryof electric shock and a loudspeaker for presentation of auditorystimuli. Each trial consists of a fifteen-second warning tone,(conditioned stimulus), continuing for an additional fifteen secondsaccompanied by electric shock (unconditioned stimulus; 1.0 mA, 350V.A.C.). The rats can terminate a trial at any point by depression ofthe response lever. A response during the initial fifteen-second warningtone ends the trial before shock delivery and is considered an avoidanceresponse, while a response occurring during shock delivery is an escaperesponse. Trials are presented every two minutes during a one-hour testsession (30 trials per session).

Trained rats maintain a reliable control baseline of avoidance behavior(zero to three avoidance failures per session). Compounds areadministered at appropriate pretreatment times to a miminum of three tofour rats at each dose level over a range of doses. Rats receive vehiclealone, during control sessions. One control and one experimental sessionare alternated during each week.

The session is divided into three consecutive twenty minute (ten trial)segments. Response counts are summed over all subjects at a given dosewithin each segment.

The number of trials in which the rats failed to exhibit an avoidanceresponse (avoidance block; AB) or failed to exhibit an escape response(escape block; EB) is determined for the segment displaying the maximumsuch effect at each dose. This number is expressed as a percentage ofthe total trials within the segment. The dose calculated to produce a50% block of avoidance (ABD 50) is obtained from the dose-effectregression line fitted by the Method of Least Squares. The lowest dosewhich produced a 20% block of escape responding (EBD 20) is read from agrphic dose-effect plot. In obtaining these values, percent effect isplotted against the log dose.

Antipsychotic agents can be distinguished from other types of drugs,which affect the behavior of rats in this procedure, by the largerseparation between doses which block avoidance responding and doseswhich block escape responding. The clinical potency of antipsychoticdrugs with known therapeutic uses and properties is significantly andhighly correlated with their potency in this procedure. Consequently,the compounds of formula A may be used therapeutically in dosage rangesconsistent with their potency in the test procedure.

When2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]-pyrrolo[2,3-g]isoquinolin-10(10H)-oneis utilized as the test substance, neuroleptic activity is observed atan ABD₅₀ of 0.98 mg/kg p.o.

Similarly, when2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-oneis utilized as the test substance, neuroleptic activity is observed atan ABD₅₀ of 0.15 mg/kg p.o.

Similarly, when2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-oneis utilized as the test substance, neuroleptic activity is observed atan ABD₅₀ of 0.73 mg/kg p.o.

Similarly, when2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,hydrochloride, 0.75 molar hydrate, which has demonstrated an LD₅₀ of,for example, 650 mg/kg p.o. in mice, is utilized as the test substance,neuroleptic activity is observed at an ABD₅₀ of 5.5 mg/kg p.o.

Similarly, when2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-oneis utilized as the test substance, neuroleptic activity is observed at 8mg/kg p.o. where the avoidance blockade is 63%.

Similarly, when2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-oneis utilized as the test substance, neuroleptic activity is observed at16 mg/kg p.o. where the avoidance blockade is 50%.

The compounds of formula A and their pharmaceutically acceptable acidaddition salts have antipsychotic effects which are qualitativelysimilar to those of haloperidol, and trifluoroperazine, known for theirtherapeutic uses and properties. Thus, the compounds of formula Ademonstrate a pattern of activity associated with antipsychotic drugs ofknown efficacy and safety.

The compounds of formula A and their pharmaceutically acceptable acidaddition salts can be used in the form of conventional pharmaceuticalpreparations. By way of exemplification, suitable oral dosage unitscomprise or are in the range of from 0.05 to 50 mg., and suitable oraldosage regimens in warm-blooded animals comprise or are in the range offrom about 0.001 mg/kg per day to about 10 mg/kg per day. However, forany particular warm-blooded animal, the specific dosage regimen may bevariable and should be adjusted according to individual need and theprofessional judgement of the person administering or supervising theadministration of a compound of formula A or a pharmaceuticallyacceptable acid addition salt thereof. Furthermore, the frequency withwhich any such dosage form will be administered will vary, dependingupon the quantity of active medicament present therein and the needs andrequirements of the pharmacological situation.

For the disclosed use, the compounds of formula A and theirpharmaceutically acceptable acid addition salts are formulated, usingconventional inert pharmaceutical adjuvant materials, into dosage formswhich are suitable for oral or parenteral administration. Such dosageforms include tablets, suspensions, solutions, and the like.Furthermore, the compounds of formula A can be embodied into, andadministered in the form of, suitable hard or soft capsules. Theidentity of the inert adjuvant materials which are used in formulatingthe compounds of formula A and their pharmaceutically acceptable acidaddition salts into oral and parenteral dosage forms will be immediatelyapparent to persons skilled in the art. These adjuvant materials, eitherinorganic or organic in nature, include, for example, water, gelatin,lactose, starch, magnesium stearate, talc, vegetable oils, gums,polyalkylene glycols, etc. Moreover, preservatives, stabilizers, wettingagents, emulsifying agents, salts for altering osmotic pressure,buffers, or the like, can be incorporated, if desired, into suchformulations.

Since the compounds of formula A and their pharmaceutically acceptableacid addition salts possess asymmetric carbon atoms, they are ordinarilyobtained as racemic mixtures. If desired, diastereomeric mixtures, whenobtained, may be separated. The resolution of individual racemates intothe optically active isomers can be carried out by known procedures.Alternatively, optically active isomers can be prepared utilizing, inthe processes herein described, corresponding optically active startingmaterials. Some racemic mixtures can be precipitated as eutectics andcan thereafter be separated. Chemical resolution is, however, preferred.By this method, diastereomers are formed from the racemic mixture withan optically active resolving agent, for example, an optically activeacid, such as (+)-tartaric acid, (+)-dibenzoyl-D-tartaric acid,(+)-d-10-camphor-sulfonic acid, (-)-3-pinanecarboxylic acid, and thelike, to form a diastereomeric salt. The formed diastereomers areseparated by fractional crystallization and can be converted to thecorresponding optical isomer base. Thus, the invention covers theoptically active isomers of the compounds of formula A as well as theirracemates.

Furthermore, due to the possible different spatial arrangements of theiratoms, it is to be understood that the compounds of this invention maybe obtained in more than one possible geometric isomeric form. Thecompounds of formula A, as described and claimed, are intended toembrace all such isomeric forms. Accordingly, the examples includedherein are to be understood as illustrative of particular mixtures ofgeometric isomers or single geometric isomers and not as limitationsupon the scope of the invention.

The Examples which follow further illustrate the invention. Alltemperatures are in degrees Centigrade, unless otherwise stated.

EXAMPLE 1 Preparation ofN-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine

185.2 g. of N-methyl-(3,5-dimethoxyphenyl)-ethylamine hydrochloride wasdissolved in 1600 ml. of water and the solution was made alkaline with160 ml. of ammonium hydroxide. The mixture was extracted with 3×1000 ml.of dichloromethane and the combined extracts were washed with 1000 ml.of brine and dried over anhydrous sodium sulfate. Evaporation of thesolvent on a rotary evaporator at 35°-40° gave 156.0 g. of free base.

In a 12 l. 3-neck flask equipped with a mechanical stirrer and two dryice condensers, one fitted with a gas inlet and the other with asoda-lime drying tube was condensed 4.0 l. of anhydrous ammonia. To theammonia was added a solution of 156.0 g. of the free base in 400 ml. oft-butanol and 400 ml. of anhydrous ether over 15 minutes. To the stirredsolution was added over 50 min. a total of 33.6 g. of lithium wire cutinto 2.5 in. lengths. The addition rate was controlled so that 5 in. ofwire was added per minute. After all the lithium had been added, thedeep blue mixture was stirred under reflux for 2 hours. Then 2.8 l. ofanhydrous ether was added to dilute the mixture, the drying tube wasremoved to allow the hydrogen to vent, and a total of 280 g. of ammoniumchloride powder was added slowly over 30 minutes until the blue colorhad dissipated. The dry ice condenser was removed and the mixture wasstirred and the ammonia allowed to evaporate overnight. To the residuewas added 2.8 l. of ice water. The mixture was transferred to aseparatory funnel, rinsing with 800 ml. of ether, and the layers wereseparated. The aqueous layer was extracted with 2×1.5 l. ofdichloromethane and the extracts were combined and washed with 1 l. ofbrine and dried over anhydrous sodium sulfate. Evaporation of thesolvents on a rotary evaporator at 40° and finally at 40°/1.0 mm. for1.5 hours afforded 150.7 g. of crude product as a yellow oil. The crudeoil was distilled through a 12-in. Goodloe column (bath 150°) collectingfractions as follows:

    ______________________________________                                        Fraction bp             wt         ge purity                                  ______________________________________                                        1        40-80°/0.45 mm.                                                                       7.9 g.     4.6%                                       2        80-85°/0.45 to 0.15 mm.                                                               6.2 g.     50%                                        3        85-86°/0.15 mm.                                                                       21.2 g.    92%                                        4        86-87°/0.15 mm.                                                                       99.4 g.    100%                                       ______________________________________                                    

Fractions 3 and 4 combined afforded 120.6 g. ofN-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine as a colorlessoil.

Anal. Calcd. for C₁₁ H₁₉ NO₂ : C, 66.97; H, 9.71; N, 7.10. Found: C,66.84; H, 9.62; N, 6.93.

EXAMPLE 2 Preparation of1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-one

A mixture of 15.6 g. ofN-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (79 mmol), 16.7g. of 2-isonitrosocyclohexanone (131 mmol), and 19.5 g. of zinc dust(300 mg-atom) in 300 ml. of 70% aqueous acetic acid heated to reflux for5 hours, and was cooled and filtered. The filtrate was concentrated invacuo and excess dioxane was added. The dioxane-acetic acid azeotropewas distilled off and the process was repeated until all the acetic acidwas removed. The residue was chromatographed on Alumina III eluting with10% methanol in dichloromethane to give 10.7 g. of crude1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-one.The crude product was dissolved in methanol and treated with methanolicHCl and the solvent evaporated to give 12.2 g. of1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-onehydrochloride.

EXAMPLE 3 Preparation of2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-(11(11H)-one

A mixture of 2.3 g. of1,2,3,5,6,7,8,9-octahydro-2-[2-(methylamino)ethyl]-4H-carbazol-4-onehydrochloride (8.14 mmol) and 2.3 g. of paraformaldehyde (76 mmol) in100 ml. of n-butanol was heated in a pressure bottle immersed in a 180°C. oil bath to an internal pressure of 80 psi for 1 hour. The solutionwas cooled and the solvent was removed at reduced pressure and theresidue was dissolved in water and washed with dichloromethane(discarded). The aqueous solution was made alkaline with ammoniumhydroxide and extracted with dichloromethane. The extracts were driedover sodium sulfate, filtered, and evaporated to a 10 ml. volume. Themixture was slurried with 10 g. of alumina, filtered, and evaporated todryness. The residue was chromatographed on 80 g. of Alumina III elutingwith 10% methanol in dichloromethane to give crude2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-onecontaining a small amount of the corresponding 4a,11a-cis isomer.Crystallization of the crude product from methanol-dichloromethane-ethergave2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]-pyrrolo[2,3-g]isoquinolin-11(11H)-oneas an off-white solid. The free base was treated with HCl in methanoland the hydrochloride recrystallized twice from ethanol to give 0.46 g.of pure2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,hydrochloride, 0.75 molar hydrate as crystals, mp 217°-220° (19% yield).

Anal. Calcd. for C₁₆ H₂₂ N₂ O.HCl.0.75H₂ O: C, 62.33; H, 8.01; N, 9.09;Cl, 11.50. Found: C, 62.56; H, 8.11; N, 9.08; Cl, 11.59.

EXAMPLE 4 Preparation of3,4-dihydro-1H-6,8-dimethoxy-2-methyl-isoquinoline, hydrochloride

A solution of N-methyl-(3,5-dimethoxyphenyl)ethylamine hydrochloride(15.0 g, 64.7 mmol) in 30 ml. of water was treated with 35 ml. of 2 Nsodium hydroxide and extracted with dichloromethane. The combinedextracts were concentrated on a rotary evaporator and mixed with aqueousformaldehyde (65 ml, 37% solution). The mixture was refluxed for 2hours, made alkaline with 2 N sodium hydroxide (15 ml.) and extractedwith dichloromethane. The combined extracts were washed with brine anddried over anhydrous magnesium sulfate and concentrated to give theproduct as a yellow oil (15.5 g). The oil was dissolved in 100 ml. ofethanol and treated with ethanolic hydrogen chloride. Ether (75 ml) wasadded, and the salt crystallized to give 10.15 g. of3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline, hydrochloride (64%yield).

EXAMPLE 5 Preparation of1,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline andoctahydro-2-methylisoquinolin-6,8-dione

Ammonia (150 ml) was condensed in a flask containing t-butanol (9.1 g,123 mmol) and diethyl ether (50 ml). To the solution was added3,4-dihydro-1H-6,8-dimethoxy-2-methylisoquinoline hydrochloride (1.0 g,4.1 mmol). After stirring 2-3 minutes, lithium wire (0.57 g, 82 mmol)was added in short pieces over 30 minutes. The blue solution was stirredunder reflux for 2.5 hours and solid ammonia chloride (4.5 g) was addeduntil the blue color dissipated. Ether (100 ml) was added and theammonia was allowed to evaporate overnight. Ice water (100 ml) was addedand the organic phase was separated. The aqueous layer was extractedwith ethyl acetate and chloroform. The combined extracts were washedwith brine and dried over anhydrous magnesium sulfate and concentratedto give 1,2,3,4,4a,7-hexahydro-6,8-dimethoxy-2-methylisoquinoline (0.58g, crude) as a yellow oil.

The crude product (1.05 g) in 20 ml. of 70% aqueous acetic acid wasrefluxed for 5 hours and the acetic acid was removed on a rotaryevaporator. The residue was dissolved in water and washed withchloroform. The aqueous phase was concentrated to a 10 ml. volume andchromatographed on Dowex AG 50 WX8 eluting with 2 molar aqueous pyridineto afford 0.11 g. of octahydro-2-methylisoquinolin-6,8-dione (11.6%yield) as a light yellow solid. Treatment with hydrochloric acid inmethanol afforded the hydrochloride, mp 193°-196°.

EXAMPLE 6 Preparation of2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-onevia octahydro-2-methylisoquinolin-6,8-dione

A mixture of 72 g. of crude octahydro-2-methylisoquinolin-6,8-dione(about 30% pure, approximately 0.1 mol), 21.1 g. of crude2-isonitrosocyclohexanone (about 60% pure, approximately 0.1 mol), and19.5 g. of zinc dust (0.3 g-atom) in 500 ml. of 70% aqueous acetic acidwas heated to reflux for 1 hour. A second 10.5 g. portion of2-isonitrosocyclohexanone and 6.5 g. of zinc dust was added and themixture refluxed an additional 2 hours. The solution was cooled,filtered and concentrated in vacuo, and the residue was dissolved inwater and washed with chloroform (discarded). The aqueous solution wasmade alkaline with ammonium hydroxide and was extracted with chloroform.The extracts were washed with brine, dried over sodium sulfate, andconcentrated. The crude2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11,11H-onewas chromatographed on silica gel (dry column) eluting with the organicphase of a mixture prepared by shaking (by volume) 90 parts chloroform,30 parts methanol, 10 parts water, and 6 parts acetic acid to give 7.8g. of2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-oneas a white amorphous solid after slurrying with hot ethanol, mp273°-275° C. (dec.).

Anal. Calcd. for C₁₆ H₂₂ N₂ O: C, 74.38; H, 8.58; N, 10.84. Found: C,74.21; H, 8.39; N, 10.61.

EXAMPLE 7

Following the procedure of Example 6, starting from2-isonitrosocyclopentanone and octahydro-2-methylisoquinolin-6,8-dione,there was obtained2-methyl-1,2,3,4,4,a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 296°-297° C. (dec.), crystallized from ethanol-methanol.

Anal. Calcd. for C₁₅ H₂₀ N₂ O: C, 73.74; H, 8.25; N, 11.47. Found: C,73.93; H, 8.41; N, 11.46.

The hydrochloride crystallized from water as a hemihydrate, mp 256°-258°C. (dec.)

Anal. Calcd. for C₁₅ H₂₀ N₂ O.HCl0.5H₂ O: C, 62.17; H, 7.65; N, 9.67;Cl, 12.23. Found: C, 62.16; H, 7.71; N, 9.54; Cl, 12.37.

EXAMPLE 8

Following the procedure of Example 6, starting from2-isonitrosocycloheptanone and octahydro-2-methylisoquinolin-6,8-dione,there was obtained2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one,mp 293°-296° C., crystallized from ethanol.

Anal. Calcd. for C₁₇ H₂₄ N₂ O: C, 74.96; H, 8.88; N, 10.28. Found: C,74.79; H, 8.74; N, 10.33.

EXAMPLE 9

Following the procedure of Example 6, starting from2-isonitrosocyclooctanone and octahydro-2-methylisoquinolin-6,8-dione,there was obtained2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one,mp 298°-300° C., crystallized from water-dimethylformamide.

Anal. Calcd. for C₁₈ H₂₆ N₂ O: C, 75.48; H, 9.15; N, 9.78. Found: C,75.29; H, 9.04; N, 9.70.

EXAMPLE 10 Preparation of2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one

A mixture of 1.9 g. of2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,2.6 g. of ethyl chloroformate, and 3.2 g. of potassium bicarbonate in100 ml. of dioxane was heated to reflux for 6 hours, cooled, andfiltered. The filtrate was concentrated at reduced pressure, dissolvedin chloroform, and extracted with 5% aqueous hydrochloric acid, washedwith water, brine, and dried over sodium sulfate. Evaporation of thesolvent afforded 1.4 g. of the carbamate,2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.From the aqueous extracts, 0.45 g. of starting material was recovered bytreatment with ammonium hydroxide and chloroform extraction.

The crude carbamate (1.4 g.) was heated to reflux for 24 hours with 15ml. of 30% aqueous sodium hydroxide in a mixture of 15 ml. of ethanoland 5 ml. of dioxane. The mixture was concentrated in vacuo and theresidue was dissolved in 5% aqueous hydrochloric acid and washed withchloroform. The aqueous solution was made alkaline with ammoniumhydroxide and extracted with chloroform. The extracts were washed withbrine, dried, and concentrated to afford 0.65 g. of2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.

EXAMPLE 11

Following the procedure of Example 10, starting from2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,there was obtained via the carbamate,1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 242°-245° C. (dec.), crystallized from ethanol-ethyl acetate.

Anal. Calcd. for C₁₄ H₁₈ N₂ O: C, 73.01; H, 7.88; N, 12.16. Found: C,72.84; H, 7.78; N, 12.30.

EXAMPLE 12

Following the procedure of Example 10, starting from2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one,there was obtained via the carbamate,1,2,3,4,4a,5,6,7,8,9,10,11,12,13a-tetradecahydro-4a,13a-trans-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-4-one,mp 283°-5° C., crystallized from ethanol.

Anal. Calcd. for C₁₇ H₂₄ N₂ O: C, 74.96; H, 8.88; N, 10.28. Found: C,74.71; H, 8.65; N, 10.24.

EXAMPLE 13 Preparation of2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one

A mixture of 0.68 g. of2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,1.68 g. of γ-chloro-p-fluorobutyrophenone, and 1.55 g. of potassiumcarbonate in 15 ml. of diethylketone was heated to reflux for 24 hours.The mixture was cooled, filtered and concentrated. The residue waschromatographed (dry column) eluting with the organic phase of a mixtureprepared by shaking (by volume) 90 parts chloroform, 30 parts methanol,10 parts water, and 6 parts acetic acid to afford 0.85 g. of a crudeamine, which was recrystallized from ethanol to afford 0.42 g. of pure2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-oneas a crystalline solid, mp 220°-222°.

Anal. Calcd. for C₂₅ H₂₉ N₂ O₂ F: C, 73.50; H, 7.16; N, 6.86; F, 4.65.Found: C, 73.46; H, 7.08; N, 7.16; F, 4.61.

EXAMPLE 14

Following the procedure of Example 13, alkylation of2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-onewith (2-bromoethyl)benzene afforded2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,mp 250°-256° C. (dec.), as a crystalline solid after recrystallizationfrom ethanol.

Anal. Calcd. for C₂₃ H₂₈ N₂ O: C, 79.27; H, 8.10; N, 8.04. Found: C,79.29; H, 8.40; N, 7.97.

EXAMPLE 15

Following the procedure of Example 13, alkylation of2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-onewith benzyl chloride afforded2-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,mp 266°-268° C., as a crystalline solid after recrystallization fromethanol.

Anal. Calcd. for C₂₂ H₂₆ N₂ O: C, 79.00; H, 7.84; N, 8.38. Found: C,79.27; H, 8.03; N, 8.60.

EXAMPLE 16

Following the procedure of Example 13, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith benzyl chloride afforded2-benzyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 258°-260° C. (dec.), as a crystalline solid after recrystallizationfrom ethanol.

Anal. Calcd. for C₂₁ H₂₄ N₂ O: C, 78.71; H, 7.55; N, 8.74. Found: C,78.97; H, 7.54; N, 8.63.

EXAMPLE 17

Following the procedure of Example 13, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith γ-chloro-p-fluorobutyrophenone afforded2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 225°-227° C., as a crystalline solid after recrystallization fromethanol.

Anal. Calcd. for C₂₄ H₂₇ FN₂ O₂ : C, 73.07; H, 6.90; N, 7.10; F, 4.82.Found: C, 72.76; H, 6.86; N, 7.24; F, 4.71.

EXAMPLE 18

Following the procedure of Example 13, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith (2-bromoethyl)benzene afforded2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 251°-254° C. (dec.), as a crystalline solid after recrystallizationfrom ethanol.

Anal. Calcd. for C₂₂ H₂₆ N₂ O: C, 79.00; H, 7.84; N, 8.38. Found: C,78.68; H, 7.72; N, 8.28.

EXAMPLE 19

Following the procedure of Example 13, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith 4-methoxybenzyl chloride afforded2-(4-methoxybenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-4-one,mp 236°-8° (dec.), as a crystalline solid after recrystallization fromethanol.

Anal. Calcd. for C₂₂ H₂₆ N₂ O₂ : C, 75.40; H, 7.48; N, 7.99. Found: C,75.39; H, 7.41; N, 8.03.

EXAMPLE 20

Following the procedure of Example 13, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith 4-chlorobenzyl chloride afforded2-(4-chlorobenzyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-oneas a crystalline monohydrate, mp 254°-6° after recrystallization fromethanol.

Anal. Calcd. for C₂₁ H₂₃ N₂ O ClH₂ O: C, 67.63; H, 6.22; N, 7.51; Cl,9.51. Found: C, 67.86; H, 6.38; N, 7.50; Cl, 9.92.

EXAMPLE 21

Following the procedure of Example 13, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith allyl bromide afforded2-(2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 257°-9° (dec.), after recrystallization from ethyl acetate-ethanol.

Anal. Calcd. for C₁₇ H₂₂ N₂ O: C, 75.52; H, 8.20; N, 10.36. Found: C,75.25; H, 8.17; N, 10.36.

EXAMPLE 22

Following the procedure of Example 12, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith 2-bromoethyl ether afforded2-(2-ethoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 236°-8° (dec.) as a crystalline solid after recrystallization fromethanol.

Anal. Calcd. for C₁₈ H₂₆ N₂ O₂ : C, 71.49; H, 8.67; N, 9.26. Found: C,71.35; H, 8.47; N, 9.23.

EXAMPLE 23

Following the procedure of Example 13, alkylation of2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-onewith the ethylene ketal of gamma-chloro-p-fluorobutyrophenone followedby acid hydrolysis afforded2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,6,7,8,9,10,11,12,13a-tetradecahydro-4a,13a-trans-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one.

EXAMPLE 24

Following the procedure of Example 13, the compounds listed in Table Imay be prepared from the indicatedcycloalka[4,5]pyrrolo[2,3-g]isoquinoline and the indicated halide.

                                      TABLE I                                     __________________________________________________________________________     ##STR27##                                                                    Example                                                                            Name                         n R.sub.2        X                          __________________________________________________________________________    24   2-ethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-                                                  3 CH.sub.3 CH.sub.2                                                                            Br                              cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one                     25   2-(2-acetoxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,10a-trans-6H-         cyclopenta[4,5]pyrrolo[2,3-g]isoquino- lin-10(10H)-one                                                     3                                                                                ##STR28##     Br                         26    2-[3-(4-fluorophenyl)-3-oxopropyl]-1,2,3,4,4a,5,7,8,9,10a- decahydro         -4a,10a-trans-6H-cyclopenta[4,5]pyrrolo- [2,3-g]isoquinolin-10(10H)-o         ne                           3                                                                                ##STR29##     Cl                         27   2-cyclopropylmethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,10a-trans-6H         -cyclopenta[4,5]pyrrolo[2,3-g]iso- quinolin-10(10H)-one                                                    3                                                                                ##STR30##     Cl                         28   2-propargyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-                                                       3 HCCCH.sub.2    Br                              trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-                            10(10H)-one                                                              29   2-[2-(2-thienyl)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,10a-trans         -6H-cyclopenta[4,5]pyrrolo[2,3-g]iso- quinolin-10(10H)-one                                                 3                                                                                ##STR31##     Br                         30   2-[2-(2-furyl)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-                 trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin- 10(10H)-one                                             3                                                                                ##STR32##     Br                         31   2-[2-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl]- 1,2,3,4,4a,5,7,8         ,9,10a-decahydro-4a,10a-trans-6H-cyclo- penta[4,5]pyrrolo[2,3-g]isoqu         inolin-10(10H)-one           3                                                                                ##STR33##     Br                         32   2-[2-(benzyloxy)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,10a-trans         -6H-cyclopenta[4,5]pyrrolo[2,3-g]iso- quinolin-10(10H)-one                                                 3                                                                                ##STR34##     Br                         33   2-(3-phenyl-2-propenyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro- 4a,10a-tran         s-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquino- lin-10(10H)-one                                                3                                                                                ##STR35##     Br                         34   2-[2-(ethenyloxy)ethyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-                                                  3 CH.sub.2CHOCH.sub.2 CH.sub.2                                                                 Br                              4a,10a-trans-6H-cyclopenta[4,5] pyrrolo[2,3-g]isoquino-                       lin-10(10H)-one                                                          35   2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-                                                       4 CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2                                                         Br                              4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]-                              isoquinolin-11(11H)-one                                                  36   2-cyclobutylmethyl-2,3,4,4a,5,7,8,9,10,11a-decahydro- 4a,11a-trans-1H         ,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso- quinolin-11(11H)-one                                                  4                                                                                ##STR36##     Br                         37   2-[2-(2-thienyl)ethyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro- 4a,11a-tran         s-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso- quinolin-11(11H)-one                                              4                                                                                ##STR37##     Br                         38   2-[2-(2-furyl)ethyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro- 4a,11a-trans-         1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]iso- quinolin-11(11H)-one                                                4                                                                                ##STR38##     Br                         39   2-[3-(4-fluorophenyl)-3-oxopropyl]-2,3,4,4a,5,7,8,9,10,11a- decahydro         -4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo- [2,3-g]isoquinolin-11(11H)         -one                         4                                                                                ##STR39##     Cl                         40   2-(2-propenyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-                                                   4 CH.sub.2CHCH.sub.2                                                                           Br                              trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquino-                             lin-11(11H)-one                                                          41   2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro- 4a,11a-trans-1         H,6H-cyclohexa[4,5]pyrrolo[2,3-g]- isoquinolin-11(11H)-one                                                 4                                                                                ##STR40##     Br                         42   2-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]- 2,3,4,4a,5,7,8,         9,10,11a-decahydro-4a,11a-trans-1H,6H- cyclohexa[4,5]                         pyrrolo[2,3-g]isoquinolin-11(11H)-one                                                                      4                                                                                ##STR41##     Br                         43   2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10,- 11,12a-dode         cahydro-4a,12a-trans-6H-cyclohepta[4,5]- pyrrolo[2,3-g]isoquinolin-12         (12H)-one                    5                                                                                ##STR42##     Cl                         44   2-(3-phenoxypropyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-                 4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin- 12(12H)-one                                      5                                                                                ##STR43##     Br                         45   2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro- 4a,12a-tr         ans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin- 12(12H)-one                                               5                                                                                ##STR44##     Br                         46   2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodeca- hydro-4a,13a-         trans-1H,6H-cycloocta[4,5]pyrrolo- [2,3-g]isoquinolin-13(13H)-one                                          6                                                                                ##STR45##     Br                         47   2-(2-ethoxyethyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-dodeca-                                                    6 CH.sub.3 CH.sub.2 OCH.sub.2 CH.sub.2                                                         Br                              hydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo-                               [2,3-g]isoquinolin-13(13H)-one                                           48   2-(3-phenoxypropyl)-2,3,4,4a,5,7,8,9,10,11,12,13a-do- decahydro-4a,13         a-trans-1H,6H-cycloocta[4,5]- pyrrolo[2,3-g]isoquinolin-13(13H)-one                                        6                                                                                ##STR46##     Br                         __________________________________________________________________________

EXAMPLE 49 Preparation of2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione

A mixture of 244 mg. (1.0 mmol) of2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-oneand 222 mg. (1.0 mmol) of phosphorus pentasulfide in 15 ml. of dioxanewas stirred and refluxed for 17 hours. The dioxane solution was decantedoff and water (20 ml.) and enough ammonium hydroxide to bring the pH to8-9 was added to the residue. The mixture was extracted with chloroform,and the extracts were washed with brine, dried and evaporated. The crudethione was chromatographed as described in Example 13 to afford 65 mg.of pure solid thione which was recrystallized from acetonitrile to give2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione,mp 224°-227° C. (dec.).

Anal. Calcd. for C₁₅ H₂₀ N₂ S: C, 69.19; H, 7.74; N, 10.76. Found: C,68.97; H, 7.59; N, 10.97.

EXAMPLE 50

The procedure of Example 50 is used to prepare2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-thionestarting from2-methyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.

EXAMPLE 51

The procedure of Example 50 is used to prepare1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thionestarting from1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.

EXAMPLE 52

The procedure of Example 13 is used to prepare2-[4-(4-fluorophenyl-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thionestarting from1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thioneand γ-chloro-p-fluorobutyrophenone.

EXAMPLE 53

The procedure of Example 13 is used to prepare2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thionestarting from1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thioneand (2-bromoethyl)benzene.

EXAMPLE 54 Preparation of6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one

To a mixture of 244 mg. (1.0 mmol) of2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onein 10 ml. of dry tetrahydrofuran at -30° is added 0.5 ml. ofn-butyllithium (1.1 mmol of 2.2 M solution in hexane) over 2-3 minutesvia syringe. The solution is stirred for 30 minutes at -30° and 168 mg.of benzoyl chloride (1.2 mmol) is added over 2-3 minutes. The solutionis stirred 1 hour at -30° and 30 minutes at room temperature. Themixture is poured onto ice and extracted with chloroform. The extractsare washed with brine, dried (sodium sulfate), concentrated andchromatographed to afford the6-benzoyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.

EXAMPLE 55

Following the procedure of Example 54,2,6-dimethyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-oneis prepared using methyl iodide instead of benzoyl chloride.

EXAMPLE 56 Preparation of2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one

A solution of 488 mg. (2.0 mmol) of2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-oneand 300 mg. (3.0 mmol) of 3,3-dimethyl-1,2-epoxybutane in 15 ml. ofmethanol was refluxed for 24 hours and concentrated. The residue waschromatographed, and the crude product (350 mg.) crystallized fromethanol to give 200 mg. of2-(2-hydroxy-3,3-dimethylbutyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one,mp 276°-278° C. (dec.).

Anal. Calcd. for C₂₁ H₃₂ N₂ O₂ : C, 73.22; H, 9.36; N, 8.13. Found: C,73.39; H, 9.31; N, 8.15.

EXAMPLE 57

The procedure of Example 56 is used to prepare2-(2-hydroxy-2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onestarting from1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-oneand styrene oxide.

EXAMPLE 58

Following the procedure of Example 56, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith ethylene oxide at room temperature afforded2-(2-hydroxyethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 237°-9° (dec.) as a crystalline solid after recrystallization fromethanol.

Anal. Calcd. for C₁₆ H₂₂ N₂ O₂ : C, 70.04; H, 8.08; N, 10.21. Found: C,69.66; H, 8.17; N, 10.19.

EXAMPLE 59

Following the procedure of Example 56, alkylation of1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onewith 3,3-dimethyl-1,2-epoxybutane afforded2-(2-hydroxy-3,3-dimethylbutyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 284°-6° (dec.), as a crystalline solid after recrystallization fromethanol.

Anal. Calcd. for C₂₀ H₃₀ N₂ O₂ : C, 72.69; H, 9.15; N, 8.48. Found: C,72.80; H, 9.02; N, 8.55.

EXAMPLE 60

A mixture of 30 mg of sodium hydride dispersion (57%, washed free ofoil) and 2 ml of dry dimethyl sulfoxide (DMSO) was heated to 65°-70° for1.5 hrs. The solution was cooled and a solution of 244 mg of2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onein 1 ml of dry DMSO was added in portions. The mixture was stirred for 2hrs. at room temperature. A solution of 160 mg of benzyl chloride in 1ml of dry DMSO was added, and the mixture was stirred for 2.5 hrs. atroom temperature and then poured into ice water. The mixture wasextracted with chloroform, the extracts washed with brine, dried andconcentrated to give 560 mg crude solid. Chromatography on silica gelusing the system given in Example 62 gave 60 mg of6-benzyl-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one as a crystallinesolid, mp 169°-171° after recrystallization from ethyl acetate-ethanol.

Anal. Calcd. for C₂₂ H₂₆ N₂ O: C, 79.00; H, 7.84; N, 8.35. Found: C,78.92; H, 7.84; N, 8.55.

EXAMPLE 61

To a solution of 2.35 g ofrac.-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-onein 20 ml of methanol was added a solution of 3.62 g of(+)-dibenzoyl-(D)-tartaric acid monohydrate in 20 ml of methanol. Themixture was concentrated and crystallized from methanol three times andconverted to the free base with ammonium hydroxide. Recrystallization ofthe base from ethanol afforded 0.18 g of(-)-2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one,mp 270°-2° (dec.). The hydrochloride salt gave [α]_(D) ²⁵ -101.17° inmethanol (1%).

EXAMPLE 62

Preparation of2-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.

A mixture of 394 mg (1.0 mmol) of2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-oneand 151 mg of sodium borohydride (4.0 mmol) in 15 ml of ethanol wasstirred at room temperature for 24 hrs. A second portion of sodiumborohydride (150 mg, 4.0 mmol) was added, and the mixture was stirredfurther at room temperature for 24 hrs. The mixture was poured into 50ml of water and filtered to remove the white solid product containingsome starting material. Dry column chromatography on silica gel elutingwith the lower phase of a mixture of 90 ml chloroform, 30 ml methanol,10 ml water and 6 ml acetic acid afforded 220 mg of solid which wasrecrystallized from aqueous dimethylformamide to give2-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-6H-4a,10a-trans-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, mp243°-5°, as a mixture of diastereomers.

Anal. Calcd. for C₂₄ H₂₉ N₂ O₂ F: C, 72.70; H, 7.37; N, 7.07. Found: C,72.68; H, 7.56; N, 7.33.

EXAMPLE 63

Following the procedure of Example 62, sodium borohydride reduction of2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-oneafforded2[4-(4-fluorophenyl)-4-hydroxybutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo-[2,3-g]isoquinolin-11(11H)-one,as a mixture of diastereomers, mp 239°-41°, crystallized from1,4-dioxane.

Anal. Calcd. for C₂₅ H₃₁ N₂ O₂ F: C, 73.14; H, 7.61; N, 6.82. Found: C,73.18, H, 7.72; N, 6.82.

EXAMPLE 64

Following the procedure of Example 62, sodium borohydride reduction of2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-oneafforded2-[4-(4-fluorophenyl)-4-hydroxybutyl]-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one,as a mixture of diastereomers, mp 249°-51°, crystallized from1,4-dioxane.

Anal. Calcd. for C₂₇ H₃₅ N₂ O₂ F: C, 73.94; H, 8.04; N, 6.39. Found: C,73.71; H, 8.05; N, 6.37.

EXAMPLE 65 Preparation of 5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione

To a stirred solution ofN-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (5.5 g, 27.9mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6 N hydrochloricacid in one portion. The warm solution was heated for 15 min. at 50° C.and concentrated to give a light yellow oil. The crude oil was dissolvedin 25 ml of water, and the solution was mixed with 50 g of Dowex 50X8resin (previously washed with 2 N HCl and deionized water) in a sinteredglass funnel. After a few minutes, the aqueous solution was drawn out bysuction, and the resin rinsed with four 50 ml-portions of water, andthen with eight 35 ml-portions of 2 M aqueous pyridine. Pyridinefractions 3-8 were pooled and concentrated to give 3.9 g of5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione. An analytical samplecrystallized from water and had mp 171°-4° C.

Anal. Calcd. for C₉ H₁₅ NO₂ : C, 63.88; H, 8.93; N, 8.28. Found: C,63.50; H, 8.87; N, 8.15.

EXAMPLE 66 Preparation of6-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one

Following the procedure of example 60, 316 mg of2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-onewas alkylated with 190 mg of benzyl chloride to afford6-benzyl-2-ethoxycarbonyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one(220 mg), mp 54°-60° C., which was hydrolyzed following the procedure ofexample 10 with sodium hydroxide to afford 80 mg of6-benzyl-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.

    __________________________________________________________________________    Capsule Formulation                                                                                    mg/capsule                                           Ingredients              0.1  0.5  5.0  10.0 25.0                             __________________________________________________________________________    2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-                     decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-                             [2,3-g]isoquinolin-10(10H)-one                                                                         0.1  0.5  5.0  10.0 25.0                             Lactose                  183.9                                                                              183.5                                                                              179.0                                                                              218.0                                                                              257.0                            Starch                   30.0 30.0 30.0 50.0 70.0                             Talc                     5.0  5.0  5.0  10.0 15.0                             Magnesium Stearate       1.0  1.0  1.0  2.0  3.0                              Total                    220 mg.                                                                            220 mg.                                                                            220 mg.                                                                            290 mg.                                                                            370 mg.                          __________________________________________________________________________     Procedure:                                                                    Mix                                                                           2[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-    rans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, lactose and     starch in a suitable mixer. Mill through a suitable mill. Mix with talc       and magnesium stearate and fill on capsule machine.                      

    __________________________________________________________________________    Tablet Formulation (Direct Compression)                                                                mg/capsule                                           Ingredients              0.1  0.5  5.0  10.0 25.0                             __________________________________________________________________________    2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-                     decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-                             [2,3-g]isoquinolin-10(10H)-one                                                                         0.1  0.5  5.0  10.0 25.0                             Lactose                  85.4 85.5 81.0 103.0                                                                              112.5                            Avicel                   30.0 30.0 30.0 45.0 60.0                             Modified Starch          8    7.5  7.5  10.0 15.0                             Magnesium Stearate       1.5  1.5  1.5  2.0  2.5                              Total                    125 mg.                                                                            125 mg.                                                                            125 mg.                                                                            170 mg.                                                                            215 mg.                          __________________________________________________________________________     Procedure:                                                                    Mix                                                                           2[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-    rans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, lactose,         avicel, and modified starch in a suitable mixer for 10-15 minutes. Add th     magnesium stearate as a premix and mix for 4 minutes. Compress on a           suitable press.                                                          

    __________________________________________________________________________    Tablet Formulation (Wet Granulation)                                                                   mg/tablet                                            Ingredients              0.1  0.5  5.0  10.0 25.0                             __________________________________________________________________________    2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-                     decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo-                             [2,3-g]isoquinolin-10(10H)-one                                                                         0.1  0.5  5.0  10.0 25.0                             Lactose                  103.9                                                                              103.5                                                                              99.0 148.0                                                                              197.0                            Modified Starch          10.0 10.0 10.0 20.0 30.0                             Pregelatinized Starch    10.0 10.0 10.0 20.0 30.0                             Magnesium Stearate       1.0  1.0  1.0  2.0  3.0                              Total                    125 mg.                                                                            125 mg.                                                                            125 mg.                                                                            200 mg.                                                                            285 mg.                          __________________________________________________________________________     Procedure:                                                                    Mix                                                                           2[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-    rans-6H-cyclopenta-[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one, lactose,        modified starch and pregelatinized starch in a suitable mixer, granulate      with water. Dry, mill. Mix with the magnesium stearate and compress on a      suitable press.                                                          

We claim:
 1. A compound of the formula ##STR47## wherein R₁ is hydrogen;alkyl of 1 to 7 carbon atoms; alkanoyl of 1 to 7 carbon atoms; benzoyl;fluorobenzoyl; phenyl or phenyl substituted by halogen, trifluoromethyl,alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro,amino, alkylamino of 1 to 7 carbon atoms or di-alkyl amino of 1 to 7carbon atoms, wherein phenyl or substituted phenyl is linked to analkylene of 1 to 4 carbon atoms;R₂ is hydrogen; alkyl of 1 to 7 carbonatoms; hydroxyalkyl of 1 to 7 carbon atoms; hydroxyalkyl of 1 to 7carbon atoms bearing as a substituent phenyl or phenyl substituted byhalogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7carbon atoms, nitro, amino, alkylamino of 1 to 7 carbon atoms ordi-alkylamino of 1 to 7 carbon atoms; alkoxyalkyl wherein each alkylgroup is of 1 to 7 carbon atoms; alkanoyloxy of 1 to 7 carbonatoms-alkyl of 1 to 7 carbon atoms; benzoyloxy-alkyl of 1 to 7 carbonatoms; 4-fluorobenzoyloxy-alkyl of 1 to 7 carbon atoms; alkanoyl of 1 to7 carbon atoms-alkyl of 1 to 7 carbon atoms; benzoyl alkyl of 1 to 7carbon atoms; 4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms; phenyl orphenyl substituted by halogen, trifluoromethyl, alkyl of 1 to 7 carbonatoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7carbon atoms or di-alkylamino of 1 to 7 carbon atoms, wherein phenyl orsubstituted phenyl is linked to an alkylene of 1 to 4 carbon atoms;alkenyl of 2 to 7 carbon atoms; cycloalkyl of 3 to 6 carbon atoms-alkylof 2 to 7 carbon atoms; alkynyl of 2 to 7 carbon atoms; thienyl-alkyl of1 to 7 carbon atoms; furylalkyl of 1 to 7 carbon atoms;phenylcarboxamido-alkyl of 1 to 7 carbon atoms; phenylcarboxamido-alkylof 1 to 7 carbon atoms wherein phenyl is substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms; phenyl-alkenyl of 2 to 7 carbon atoms;phenyl-alkenyl of 2 to 7 carbon atoms wherein phenyl is substituted byhalogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7carbon atoms, nitro, amino, alkylamino of 1 to 7 carbon atoms ordi-alkylamino of 1 to 7 carbon atoms; alkenyloxy of 2 to 7 carbonatoms-alkyl of 1 to 7 carbon atoms; phenyloxy-alkyl of 1 to 7 carbonatoms; phenyloxy-alkyl of 1 to 7 carbon atoms wherein phenyl issubstituted by halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms,alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7 carbonatoms or di-alkylamino of 1 to 7 carbon atoms; phenyl-alkoxy of 1 to 4carbon atoms-alkyl of 1 to 7 carbon atoms; phenyl-alkoxy of 1 to 4carbon atoms-alkyl of 1 to 7 carbon atoms wherein phenyl is substitutedby halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7 carbon atoms ordi-alkylamino of 1 to 7 carbon atoms; phenyl-N-imidazolonylalkyl of 1 to7 carbon atoms; or phenyl-N-imidazolonyl-alkyl of 1 to 7 carbon atomswherein phenyl is substituted by halogen, trifluoromethyl, alkyl of 1 to7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylaminoof 1 to 7 carbon atoms or di-alkylamino of 1 to 7 carbon atoms; X is Oor S; and n is 3, 4, 5 or 6,or its pharmaceutically acceptable acidaddition salt.
 2. A compound in accordance with claim 1, wherein X=O. 3.A compound in accordance with claim 1, wherein X=S.
 4. A compound inaccordance with claim 1, wherein n=3.
 5. A compound in accordance withclaim 4, which is trans.
 6. A compound in accordance with claim 5,wherein R₁ is hydrogen; R₂ is alkyl of 1 to 7 carbon atoms; alkoxyalkylwherein each alkyl group is of 1 to 7 carbon atoms; alkanoyl of 1 to 7carbon atoms-alkyl of 1 to 7 carbon atoms; benzoyl-alkyl of 1 to 7carbon atoms; 4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms;phenyloxy-alkyl of 1 to 7 carbon atoms; phenyloxy-alkyl of 1 to 7 carbonatoms wherein phenyl is substituted by halogen, trifluoromethyl, alkylof 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino,alkylamino of 1 to 7 carbon atoms or di-alkylamino of 1 to 7 carbonatoms; or phenyl or phenyl substituted by halogen, trifluoromethyl,alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro,amino, alkylamino of 1 to 7 carbon atoms or di-alkylamino of 1 to 7carbon atoms, wherein phenyl or substituted phenyl is linked to analkylene of 1 to 4 carbon atoms.
 7. A compound in accordance with claim6, wherein X=O.
 8. A compound in accordance with claim 7, wherein R₂ isalkyl of 1 to 7 carbon atoms.
 9. A compound in accordance with claim 7,wherein R₂ is alkoxyalkyl wherein each alkyl group is of 1 to 7 carbonatoms.
 10. A compound in accordance with claim 7, wherein R₂ is alkanoylof 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; benzoyl-alkyl of 1to 7 carbon atoms; or 4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms. 11.A compound in accordance with claim 7, wherein R₂ is phenyloxy-alkyl of1 to 7 carbon atoms; or phenyloxy-alkyl of 1 to 7 carbon atoms whereinphenyl is substituted by halogen, trifluoromethyl, alkyl of 1 to 7carbon atoms, alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of1 to 7 carbon atoms or di-alkylamino of 1 to 7 carbon atoms.
 12. Acompound in accordance with claim 7, wherein R₂ is phenyl or phenylsubstituted by halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms,alkoxy of 1 to 7 carbon atoms, nitro, amino, alkylamino of 1 to 7 carbonatoms or dialkylamino of 1 to 7 carbon atoms, wherein phenyl orsubstituted phenyl is linked to an alkylene of 1 to 4 carbon atoms. 13.A compound in accordance with claim 7,2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.14. A compound in accordance with claim 7,2-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.15. A compound in accordance with claim 7,2-(2-phenylethyl)-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-one.16. A compound in accordance with claim 6, wherein X=S.
 17. A compoundin accordance with claim 16, wherein R₂ is alkyl of 1 to 7 carbon atoms.18. A compound in accordance with claim 16, wherein R₂ is alkanoyl of 1to 7 carbon atoms-alkyl of 1 to 7 carbon atoms; benzoyl-alkyl of 1 to 7carbon atoms; or 4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms.
 19. Acompound in accordance with claim 16,2-methyl-1,2,3,4,4a,5,7,8,9,10a-decahydro-4a,10a-trans-6H-cyclopenta[4,5]pyrrolo[2,3-g]isoquinolin-10(10H)-thione.20. A compound in accordance with claim 1, wherein n=4.
 21. A compoundin accordance with claim 20 which is trans.
 22. A compound in accordancewith claim 21, wherein R₁ is hydrogen; R₂ is alkyl of 1 to 7 carbonatoms, alkoxyalkyl wherein each alkyl is of 1 to 7 carbon atoms,alkanoyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms;benzoyl-alkyl of 1 to 7 carbon atoms; 4-fluorobenzoyl-alkyl of 1 to 7carbon atoms; phenyloxy-alkyl of 1 to 7 carbon atoms; phenyloxy-alkyl of1 to 7 carbon atoms wherein phenyl is substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms; or phenyl or phenyl substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms, wherein phenyl or substituted phenyl is linkedto an alkylene of 1 to 4 carbon atoms.
 23. A compound in accordance withclaim 22, wherein X=O.
 24. A compound in accordance with claim 23,wherein R₂ is alkyl of 1 to 7 carbon atoms.
 25. A compound in accordancewith claim 23, wherein R₂ is alkanoyl of 1 to 7 carbon atoms-alkyl of 1to 7 carbon atoms; benzoyl-alkyl of 1 to 7 carbon atoms; or4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms.
 26. A compound inaccordance with claim 23, wherein R₂ is phenyl or phenyl substituted byhalogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7carbon atoms, nitro, amino, alkylamino of 1 to 7 carbon atoms ordialkylamino of 1 to 7 carbon atoms wherein phenyl or substituted phenylis linked to an alkylene of 1 to 4 carbon atoms.
 27. A compound inaccordance with claim 23,2-methyl-2,3,4,4a,5,6,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.28. A compound in accordance with claim 23,2-[4-(4-fluorophenyl)-4-oxobutyl]-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.29. A compound in accordance with claim 23,2-(2-phenylethyl)-2,3,4,4a,5,7,8,9,10,11a-decahydro-4a,11a-trans-1H,6H-cyclohexa[4,5]pyrrolo[2,3-g]isoquinolin-11(11H)-one.30. A compound in accordance with claim 22, wherein X=S.
 31. A compoundin accordance with claim 30, wherein R₂ is alkyl of 1 to 7 carbon atoms.32. A compound in accordance with claim 30, wherein R₂ is alkanoyl of 1to 7 carbon atoms--alkyl of 1 to 7carbon atoms; benzoyl-alkyl of 1 to 7carbon atoms; or 4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms.
 33. Acompound in accordance with claim 1, wherein n=5.
 34. A compound inaccordance with claim 33 which is trans.
 35. A compound in accordancewith claim 34, wherein R₁ is hydrogen; R₂ is alkyl of 1 to 7 carbonatoms, alkoxyalkyl wherein each alkyl group is of 1 to 7 carbon atoms;alkanoyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms;benzoyl-alkyl of 1 to 7 carbon atoms; 4-fluorobenzoyl-alkyl of 1 to 7carbon atoms; phenyloxy-alkyl of 1 to 7 carbon atoms; phenyloxy-alkyl of1 to 7 carbon atoms wherein phenyl is substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms; or phenyl or phenyl substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms, wherein phenyl or substituted phenyl is linkedto an alkylene of 1 to 4 carbon atoms.
 36. A compound in accordance withclaim 35, wherein X=O.
 37. A compound in accordance with claim 36,wherein R₂ is alkyl of 1 to 7 carbon atoms.
 38. A compound in accordancewith claim 36, wherein R₂ is alkanoyl of 1 to 7 carbon atoms-alkyl of 1to 7 carbon atoms; benzoyl-alkyl of 1 to 7 carbon atoms; or4-fluorobenzoyl-alkyl of 1 to 7 carbon atoms.
 39. A compound inaccordance with claim 35,2-methyl-1,2,3,4,4a,5,7,8,9,10,11,12a-dodecahydro-4a,12a-trans-6H-cyclohepta[4,5]pyrrolo[2,3-g]isoquinolin-12(12H)-one.40. A compound in accordance with claim 35, wherein X=S.
 41. A compoundin accordance with claim 40, wherein R₂ is alkyl of 1 to 7 carbon atoms.42. A compound in accordance with claim 1, wherein n=6.
 43. A compoundin accordance with claim 42, which is trans.
 44. A compound inaccordance with claim 43, wherein R₂ is hydrogen; R₂ is alkyl of 1 to 7carbon atoms; alkoxyalkyl wherein each alkyl group is of 1 to 7 carbonatoms; alkanoyl of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms;benzoyl-alkyl of 1 to 7 carbon atoms; 4-fluorobenzoyl-alkyl of 1 to 7carbon atoms; phenyloxy-alkyl of 1 to 7 carbon atoms; phenyloxy-alkyl of1 to 7 carbon atoms wherein phenyl is substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms; or phenyl or phenyl substituted by halogen,trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbonatoms, nitro, amino, alkylamino of 1 to 7 carbon atoms or di-alkylaminoof 1 to 7 carbon atoms, wherein phenyl or substituted phenyl is linkedto an alkylene of 1 to 4 carbon atoms.
 45. A compound in accordance withclaim 44, wherein X=O.
 46. A compound in accordance with claim 45,wherein R₂ is alkyl of 1 to 7 carbon atoms.
 47. A compound in accordancewith claim 45, wherein R₂ is alkanoyl of 1 to 7 carbon atoms-alkyl of 1to 7 carbon atoms; benzoyl-alkyl of 1 to 7 carbon atoms; or4-fluorobenzoyl-alkyl of 1 to 7 -carbon atoms.
 48. A compound inaccordance with claim 44,2-methyl-2,3,4,4a,5,7,8,9,10,11,12,13a-dodecahydro-4a,13a-trans-1H,6H-cycloocta[4,5]pyrrolo[2,3-g]isoquinolin-13(13H)-one.49. A compound in accordance with claim 44, wherein X=S.
 50. A compoundin accordance with claim 48, wherein R₂ is alkyl alkyl of 1 to 7 carbonatoms.
 51. A compound of the formula ##STR48## wherein n is 3, 4, 5 or6.